On Sunday, October 21st at the 2018 ACR/ARHP Annual Meeting, Dr Yoshiya Tanaka presented detailed data from Astellas’ Phase III trials of peficitinib (ASP015K) in the treatment of rheumatoid arthritis (RA). These data, which until this time had never been disclosed publicly, served as the basis for the company’s application for marketing approval in Japan.

Although peficitinib was found in the RAJ3 and RAJ4 trials to be solidly safe and effective, there was notably little that would differentiate the drug from other approved JAK inhibitors. In particular, it shares many similarities with Pfizer’s JAK inhibitor Xeljanz (tofacitinib). Despite this lack of product differentiation, Astellas has clearly decided that the clinical development of peficitinib in Japan and potentially other Asian countries is a worthy investment. However, it remains unclear whether peficitinib will be developed globally.

The RAJ3 study was conducted in Japanese, Korean, and Taiwanese patients with active RA and an inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) while the RAJ4 study enrolled Japanese patients with active RA who had shown inadequate responses to methotrexate (MTX). In both these trials, patients receiving peficitinib at either 100mg or 150mg per day, alone or in combination with csDMARDs or MTX, had significantly higher ACR20 response rates in comparison to placebo (differences ranged between 27% and 44%).

The peficitinib groups also showed significant improvement across a number of other secondary efficacy endpoints. In the RAJ4 trial, patients receiving peficitinib at 100mg or 150mg per day in combination with MTX (about 10mg weekly) also achieved the primary efficacy endpoint of significant inhibition of radiographic progression, measured using the mean mTSS change from baseline.

Although these efficacy read-outs are notable, they are highly similar to results found in the ORAL series of Phase III studies conducted for tofacitinib. Peficitinib also showed similar rates of adverse events as tofacitinib and demonstrated many of the the safety signals typical of JAK inhibitors, including a small but increased risk of serious infection, herpes zoster-related disease, and malignancy.

Developing a strategy for peficitinib

In a market like RA, which grows more stiflingly crowded every year, it is crucial for companies to strategically target their products so as to ensure a good return on investment. Development of peficitinib outside of Japan has been in flux for many years, starting with one particularly lackluster Phase IIb trial competed in 2013.

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In response, Janssen soon terminated its licensing agreement with Astellas formed in 2012, which had allotted the J&J subsidiary worldwide rights to the development of peficitinib outside of Japan. Since that time, development of peficitinib has remained stalled outside of Asia. It is likely that Astellas has been waiting on these Phase III data in order to entice new partners into a marketing agreement.

However, considering that the data from RAJ3 and RAJ4 did not suggest a significant clinical edge for peficitinib over already marketed JAK inhibitors, it is unclear what the future for global development of the drug looks like. Particularly in the US, where once-a-day Xeljanz XR is already available, peficitinib, which is also administered once daily, may not differentiate enough to be a profitable investment. Furthermore, the disappearance of any mention of Phase II development of peficitinib in the US/EU from Astellas’ July 2018 R&D overview, hints that global development of peficitinib may be stalled indefinitely.

Data from the RAJ3 and RAJ4 Phase III trials suggest that in Asian RA patients, peficitinib is safe and efficacious. However, due to the tumultuous licensing history of the drug and a lack of differentiating features in comparison to other JAK inhibitors, short-term global development of peficitinib seems unlikely.